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Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases (GST) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1, GSTT1, GSTP1, and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association. [ABSTRACT FROM AUTHOR]

High-mobility group box 1 (HMGB1) is a pleiotropic cytokine that propagates inflammation by its extracellular action of interacting with the receptor for advanced glycation end products (RAGE). Both HMGB1 and RAGE play multiple roles in the pathogenesis of a variety of inflammatory and autoimmune diseases. We investigated the association of five single-nucleotide polymorphisms (SNPs) of the HMGB1 gene (rs1412125, rs2249825, rs1045411, rs1060348, rs41369348) and four SNPs of the RAGE gene (rs1800624, rs1800625, rs2070600, rs3134940) with the susceptibility and clinical features of paediatric patients with IgA vasculitis (IgAV), also known as Henoch–Schönlein's purpura. This case‒control study included 103 children with IgAV (experimental group) and 150 age-matched healthy individuals (control group). The strength of the association between different groups and alleles or genotypes of HMGB1 and RAGE was estimated using odds ratios (ORs) and 95% confidence intervals (CIs). The HMGB1 polymorphisms rs41369348, rs1045411, rs2249825 and rs1412125 were associated with the development of generalized purpuric rash, and rs1412125 was associated with IgAV nephritis (IgAVN). The RAGE polymorphism rs2070600 might be linked to the development of arthritis in IgAV patients. There was no statistically significant association between the analysed polymorphisms and susceptibility to IgAV. This is the first study to propose an association between several HMGB1 and RAGE polymorphisms and different phenotypes in the clinical course of IgAV in a paediatric population. Further research on other polymorphisms of HMGB1 and RAGE should be conducted in a larger number of patients. [ABSTRACT FROM AUTHOR]

Studies concerning the genetic background of IgA vasculitis (IgAV), a small-vessel vasculitis occurring predominantly in childhood, have confirmed that the HLA-DRB1 gene showed a strong association with disease susceptibility. The objective was to investigate human leukocyte antigen (HLA) polymorphisms among Croatian patients with IgAV and their influence on disease susceptibility and clinical heterogeneity. Thus, 130 children with IgAV and 202 unrelated healthy individuals were enrolled in the study. Genomic DNA was extracted from whole peripheral blood, and HLA-A, -B, -DRB1 and -DQB1 gene polymorphism analysis was performed. HLA-A*03 (21.4% vs. 12.38%, p = 0.0092), HLA-B*37 (2.9% vs. 0.2%, p = 0.0054) and HLA-DRB1*12 (3.1% vs. 0.7%, p = 0.0216) alleles were significantly more frequent in IgAV patients than in controls. High-resolution typing revealed significantly higher frequency of HLA-DRB1*10:01 and -DRB1*11:03 among IgAV patients with gastrointestinal manifestations of the disease in comparison to controls (p = 0.0021 and p = 0.0301, respectively), while HLA-DRB1*14:01P occurred significantly more often in the group of patients who developed nephritis during the course of the disease (17.5% vs. 4.5%, p = 0.0006). Our results demonstrated that there is an association of HLA-A*03, HLA-B*37 and HLA-DRB1*12 alleles with susceptibility to IgAV in the examined Croatian pediatric population. Studies which aim to determine the HLA profile may contribute to the elucidation of the genetic background of autoimmune diseases, including IgAV. [ABSTRACT FROM AUTHOR]

Background/Objective: The purpose of this study was to evaluate the prevalence and severity of skin involvement in children with IgA vasculitis (IgAV) and its relationship with clinical and biochemical parameters and the risk of developing IgA vasculitis nephritis (IgAVN), the only cause of long-term morbidity and the main prognostic factor in IgAV patients. Methods: This national multicenter retrospective study included 611 patients under the age of 18 years with IgAV referred to five Croatian tertiary hospitals between 2009 and 2019. Patient data were collected from a database with systematic analysis of IgAV patients in the Croatian population. Results: Among the 611 children, 205 (33.55%) had purpura on the lower extremities, in 207 (33.88%) the rash extended on the trunk, in 149 (24.39%) it extended to the upper extremities, in 32 (5.24%) the rash was generalized, while 15 (2.47%) had the most severe skin symptoms: bullae, ulcerations, and necroses. IgAVN developed in 130 (21.28%) and persistent IgAVN (present for >3 months) in 48 (7.86%) children. Multivariate logistic regression found that presence of ulcerations and necroses (OR 3.20 [95% CI 1.03–9.91]), persistent purpura (OR 2.89 [95% CI 1.71–4.88]), and higher age (OR 1.16 [95% CI 1.09–1.23]) were significant predictors of IgAVN, whereas persistent purpura (OR 20.11 [95% CI 1.09–372.52]), male sex (OR 3.32 [95% CI 1.13–9.80]), and higher age (OR 1.15 [95% CI 1.00–1.30]) were predictors of persistent IgAVN. Among the laboratory parameters, higher serum urea (OR 1.43 [95% CI 1.03–2.00]) and reduction in activated partial thromboplastin time (OR 0.83 [95% CI 0.74–0.93]) were shown to have a significant impact on increasing the risk of persistent IgAVN. Conclusion: With increasing severity and duration of cutaneous manifestations in IgAV, the risk of developing IgAVN increases, making the prognosis worse, with a greater likelihood to need more aggressive treatment. [ABSTRACT FROM AUTHOR]

Background: We analysed clinical and biochemical parameters in predicting severe gastrointestinal (GI) manifestations in childhood IgA vasculitis (IgAV) and the risk of developing renal complications. Methods: A national multicentric retrospective study included children with IgAV reviewed in five Croatian University Centres for paediatric rheumatology in the period 2009–2019. Results: Out of 611 children, 281 (45.99%) had at least one GI manifestation, while 42 of 281 (14.95%) had the most severe GI manifestations. Using logistic regression several clinical risk factors for the severe GI manifestations were identified: generalized rash [odds ratio (OR) 2.09 (95% confidence interval (CI) 1.09–4.01)], rash extended on upper extremities (OR 2.77 (95% CI 1.43–5.34)] or face [OR 3.69 (95% CI 1.42–9.43)] and nephritis (IgAVN) [OR 4.35 (95% CI 2.23–8.50)], as well as lower values of prothrombin time (OR 0.05 (95% CI 0.01–0.62)], fibrinogen [OR 0.45 (95% CI 0.29–0.70)] and IgM [OR 0.10 (95% I 0.03–0.35)]] among the laboratory parameters. Patients with severe GI involvement more frequently had relapse of the disease [OR 2.14 (CI 1.04–4.39)] and recurrent rash [OR 2.61 (CI 1.27–5.38)]. Multivariate logistic regression found that the combination of age, GI symptoms at the beginning of IgAV and severity of GI symptoms were statistically significant predictors of IgAVN. Patients in whom IgAV has started with GI symptoms [OR 6.60 (95% CI 1.67–26.06)], older children [OR 1.22 (95% CI 1.02–1.46)] with severe GI form of IgAV (OR 5.90 (95% CI 1.12–31.15)] were particularly high-risk for developing IgAVN. Conclusion: We detected a group of older children with the onset of GI symptoms before other IgAV symptoms and severe GI form of the IgAV, with significantly higher risk for acute and chronic complications of IgAV. [ABSTRACT FROM AUTHOR]

Objectives: Research on spatial variability of the incidence of IgA vasculitis (IgAV) in children and its potential implications for elucidation of the multifactorial aetiology and pathogenesis is limited. We intended to observe spatial variability of the incidence of IgAV and IgA vasculitis-associated nephritis (IgAVN) using modern geostatistical methods, and hypothesised that their spatial distribution may be spatially clustered.Methods: Patients' data were retrospectively collected from 2009 to 2019 in five Croatian University Hospital Centres for paediatric rheumatology, and census data were used to calculate the incidence of IgAV. Using spatial empirical Bayesian smoothing, local Morans' I and local indicator of spatial autocorrelation (LISA), we performed spatial statistical analysis.Results: 596 children diagnosed with IgAV were included in this study, of which 313 (52.52%) were male. The average annual incidence proportion was estimated to be 6.79 per 100 000 children, and the prevalence of IgAVN was 19.6%. Existence of spatial autocorrelation was observed in both IgAV and IgAVN; however, clustering distribution differed. While IgAV showed clustering in Mediterranean and west continental part around cities, IgAVN was clustered in the northern Mediterranean and eastern continental part, where a linear cluster following the Drava and Danube river was observed.Conclusion: IgAV incidence in Croatia is similar to other European countries. Spatial statistical analysis showed a non-random distribution of IgAV and IgAVN. Although aetiological associations cannot be inferred, spatial analytical techniques may help in investigating and generating new hypotheses in non-communicable diseases considering possible environmental risk factors and identification of potential genetic or epigenetic diversity. [ABSTRACT FROM AUTHOR]

Background: We analysed clinical and biochemical parameters in predicting severe gastrointestinal (GI) manifestations in childhood IgA vasculitis (IgAV) and the risk of developing renal complications. Methods: A national multicentric retrospective study included children with IgAV reviewed in five Croatian University Centres for paediatric rheumatology in the period 2009–2019. Results: Out of 611 children, 281 (45.99%) had at least one GI manifestation, while 42 of 281 (14.95%) had the most severe GI manifestations. Using logistic regression several clinical risk factors for the severe GI manifestations were identified: generalized rash [odds ratio (OR) 2.09 (95% confidence interval (CI) 1.09–4.01)], rash extended on upper extremities (OR 2.77 (95% CI 1.43–5.34)] or face [OR 3.69 (95% CI 1.42–9.43)] and nephritis (IgAVN) [OR 4.35 (95% CI 2.23–8.50)], as well as lower values of prothrombin time (OR 0.05 (95% CI 0.01–0.62)], fibrinogen [OR 0.45 (95% CI 0.29–0.70)] and IgM [OR 0.10 (95% I 0.03–0.35)]] among the laboratory parameters. Patients with severe GI involvement more frequently had relapse of the disease [OR 2.14 (CI 1.04–4.39)] and recurrent rash [OR 2.61 (CI 1.27–5.38)]. Multivariate logistic regression found that the combination of age, GI symptoms at the beginning of IgAV and severity of GI symptoms were statistically significant predictors of IgAVN. Patients in whom IgAV has started with GI symptoms [OR 6.60 (95% CI 1.67–26.06)], older children [OR 1.22 (95% CI 1.02–1.46)] with severe GI form of IgAV (OR 5.90 (95% CI 1.12–31.15)] were particularly high-risk for developing IgAVN. Conclusion: We detected a group of older children with the onset of GI symptoms before other IgAV symptoms and severe GI form of the IgAV, with significantly higher risk for acute and chronic complications of IgAV. [ABSTRACT FROM AUTHOR]